Chronic alcoholism remains one of the major risk factors in the pathogenesis of cardiovascular diseases. Dose related bimodal effects of alcohol on cardiovascular system may reflect contrasting influences of light versus heavy alcohol consumption on the vascular endothelium. TNF expressed at the sites of arterial injury following balloon angioplasty suppresses endothelial cell (EC) proliferation and contributes to the development of restenosis. We have shown that in vitro exposure of EC to ethanol not only upregulates TNF transcription and expression but also synergistically exacerbates inhibitory effects of TNF on ECs. Our preliminary data indicates that chronic ethanol feeding in mice delays endothelial recovery and enhances intimal hyperplasia in denuded carotid arteries. At least, part of ethanol responses are mediated via TNF since TNFRI null mice are protected from ethanol-mediated effects on vascular endothelium. Our preliminary [unreadable] data also shows that ethanol feeding impairs neo-vascularization in the surgically induced ischemic hind limbs. Endothelial progenitor cells (EPC) have repeatedly been shown to mediate the processes of reendothelialization and neo-vascularization. Interestingly, our preliminary data indicates that kinetics and function of circulating EPCs from mice fed on alcohol is severely compromised. Considering the therapeutic potential for exploiting bone marrow derived progenitors/stem cells for cardiac repair as evident by recent surge in the number of high impact studies reported in the literature, it becomes additionally imperative to assess the effect of chronic alcohol either alone or synergistically with TNF, on the behavior and function of these progenitor cells, in vivo, especially in terms of their participation in the repair of ischemic tissue via neo-vascularization. Its our hypothesis that chronic ethanol impairs the function of EPCs and thereby negatively affect vasculogenesis and that part of ethanol effect on EPCs are mediated via the augmentation of TNF receptor l-mediated augmentation in apoptotic signaling. Using mice model of chronic ethanol feeding followed by surgically induce hind limb ischemia, we propose to verify these hypotheses under following specific aims: Specific Aim 1: Determine the effect of chronic alcohol on post-injury neovascularization and EPC kinetics and function in a mouse model of hind limb ischemia. Specific aim 2: Evaluate the contribution of TNFRI in alcohol-mediated EPC dysfunction. [unreadable] [unreadable] [unreadable]